Novel 2-r3-3a,4,7a-tetrahydro-4,7-(r1,r2-y)-r4-isoindolines and the corresponding 3a,4,5,6,7,7a-hexahydro compounds



United States Patent NOVEL 2-R -3a,4,7a-TETRAHYDRO-4,7-(R ,R -Y)-RISOINDOLINES AND THE CORRESPONDING 3a,4,5,6,7,7a-HEXAHYDRO COMPOUNDSGeorge Ireland Poos, Ambler, Pa., assignor to McNeil Laboratories,Incorporated, a corporation of Pennsylvama i No Drawing. Filed June 2,1961, Ser. No. 114,287

12 Claims. (Cl. 260-496) This is a continuation-in-part of applicationSerial No. 26,442, filed May 3, 1960, now abandoned.

This invention relates to a new series of organic compounds. Moreparticularly, it concerns 2-R -3a,4,7,7atetrahydro-4,7-(R ,R -Y)-R-isoindolines, the corresponding 3a,4,5,6,7,7a-hexahydro compounds, andtheir N- oxides, therapeutically active acid addition salts andquaternary ammonium compounds.

The compounds of the present invention are those wherein the R ,R-bearing Y is a saturated or unsaturated aliphatic group from two toseven carbon atoms, attached to the isoindoline nucleus at the4,7-positions through a single carbon atom. It may, if desired, befurther substituted by a hydroxyl group or an epoxy radical. Suitablesaturated and unsaturated aliphatic groups include alkyl, such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, or alkylene, such asmethylene, ethylene, propylene, isopropylene, butylene, isobutylene,etc. The R, substituents, other than hydrogen, are attached to theisoindolinonitrogen by means of a single carbon-nitrogen bond, and the Rsubstituents, when other than hydrogen, are attached to one or more ofthe available carbons on the ring nucleus.

R and R the same or diiierent, substituted or unsubstituted aromaticlower carbocyclic aryl radicals, such as phenyl, tolyl, or naphthyl.Substituents in these aromatic nuclei may be, for example, hydroxyl;lower alkyl radicals, e.g. methyl, ethyl, propyl, :butyl, or pentyl;lower alkoxy radicals, e.g. methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutoxy, pentoxy, isopentoxy, or hexoxy; lower alkenyloxyradicals, for example allyloxy; rox'a-lower alkoxy radicals, for example3-oxapentyloxy; halogen atoms, for example chloro, bromo, fluoro, oriodo; amino groups, especially tertiary amino groups, such as di-loweralkylamino groups, for example dimethyl-, diethyl-, or dibutyl-amino; oraminolower alkoxy groups, such as di-lower alkylamino-lower alkoxygroups, for example dimethylaminoethoxy. In these groupings, the same ordiiierent aromatic lower carbocyclic nucleus may contain identical ordifferent substituents which may occupy the same or different positionsin the nuclei. R and R may also be aliphatic, i.e. lower alkyl radicalssuch as, for example,

methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl,etc. which may, if desired, contain one or more further substituents as,for example, a hydroxy or amino group. R and R may further beheterocyclic substituents. containing from four to five carbon atomsinterrupted by oxygen, nitrogen, or sulfur linkages as, for example,pyrrolidyl, piperidyl, morpholyl, thiamorpholyl, py-ridyl, thienyl,furyl, piperazinyl, etc. and aralkyl substituents as, for example,benzyl, phenethyl.

R =hydrogem lower alkyl (as defined above) --CONH substituted orunsubstituted aromatic lower carbocyclic radical (as defined above);hydroxy-lower alkyl, as for example hydroxymethyl, hydroxyethyl,hydroxypropyl,

hydroxybutyl, 'hydroxypentyl, etc.; a heterocyclic moi- 3,100,776Patented Aug. 13, 1 963 R =any one or more of the substituents definedhereinabove for R R and R including hydrogen. Further it may be loweralkenyl, for example allyl or methallyl; lower alkynyl, for examplepropargyl; cycloalkyl, for example cyclopentyl or cyclohexyl;cycloalkyl, lower alkyl, for example cyclopentylpropyl orcyclohexylethyl. Where R is a lower hydrocarbon group such as one ofthose defined hereinabove, it may contain further substituents, such asnitro, amino, hydroxyl groups or halogen atoms. The hydroxyl groups maybe free, etherified, or esterified as, for example, methoxy or ethoxygroups. Amino or hydroxy substituents may be linked to the lowerhydrocarbon group (represented by R or they may be attached directly tothe ring, i.e. they may be R,,. be primary, secondary or tertiary amino,groupings as, for example, lower-alkylamino, or di-lower alkylamino,i.e. dimethylamino, diethylamino, N-cyclopentyl-N- methylamino,N-benZyl-N-methylamino, pyrrolidino, piperidino, 4-methylpiperidino,morpholino, thiamorpholino, piperazino, 4-methylpiperazino,4-hydroxyethylpiperazino. R may be, if desired, an oxygen atom attachedthrough single bonds to each of the 5- and 6- positions of theisoindoline nucleus. The preferred compounds in this series are thosewherein the R and R substituents are aromatic lower carhocyclic, R islower alkyl, R, is hydrogen and Y is ethylene. Therapeutically usefulacid addition salts of the compounds of this invention include thoseobtainable by reacting the base with an appropriate acid, as for examplean inorganic acid such as hydrohalic acid, i.e. hydrochloric,

, hydrobromic, or hydriodic acid; sulfuric, nitric, or thiocyanic acid;a phosphoric acid; an organic acid, such as acetic, propionic, glycolic,latic, pyruvic, oxalic, malonic, succim'c, maleic, fumaric, malic,tartaric, citric, benzoic, cinnamic, mandelic, methanesulfonic,ethanesulfonic, hydroxyethanesulfonic, benzenesulfonic,p-toluenesulfonic, salicyclic, p-aminosalicylic, 2-phenoxybenzoic orZ-acet- 'oxybenzoic acid.

The compounds of the present invention may be obtained by means of anovel, practical method, and it is intended that this method be includedwithin the scope of [the invention. In a general way, the processcomprises treating a 7-R ,R -Y-N-R -5-norbornene-R -2,3--dicarboximide,or the corresponding norbornane (the R R R and R substituents having themeanings given herein above) with a reducing reagent. Suitable for thispurpose are the di-light metal hydrides, such as alkali metal aluminumhydrides, for example lithium aluminum hydride; or alkali-metalborohydrides, for example lithium, sodium or potassium bonohydride.These hydrides may be employed in the presence of suitable solvents,such as ethers, for example diethylether, d-ibutylether, tetrahydrofuranor dioxane. The reduction may further be carried out with a variety ofreducing agents, for example catalytically activated hydrogen, e.g.hydrogen activated by a platinum,

palladium or nickel catalyst, such as platinum oxide or Raney nickel;hydrogenin statu nascendi, that is a reduction with metals and acids,e.g. iron, zinc, or tin, such as zinc and acetic acid; with alkalimetals and alcohols, e.g. sodium and ethanol, or butanol; with sodiumand moist ether; with sodium or aluminum amalgam and the appropriatesolvent, or with di-light metal hydrides such as sodium borohydride inthe presence of a catalyst, such as A101 Furthermore, the reduction maybe performed with reducing agents, such as stannous chloride, ferroussulfate, etc., or, if desired, electrolytically.

If the starting material employed contains a carboncarbon double bondeither in the ring or in the Y-position,

or both, and it is desired to remove either one or both of these doublebonds (as the case may be) this may be In either case, such substituentsmay v.5 accomplished either simultaneously with the reduction of the twocarbonyl groups or, if desired, by subsequent hydrogenation.Simultaneous reduction may be achieved by (treating the unsaturatedcompound with hydrogen in the presence of a catalyst selected from themetals of the eighth group of the periodic system, such as nickel,

' palladium, platinum, ruthenium or rhodium, which may be supported on acarrier, such as barium carbonate or charcoal. presence of a solventsuch as an alkanol for example methanol or ethanol and, if so-desired,under pressure. On the other hand, the carbonyl groups may first bereduced with a di-light metal hydride, as described above, Obviously, ifthe starting material is a norbornane wherein Y is a saturated linkage,conversion to the corresponding end product may be accomplishedchemically or cataly-tically, asdescribed above.

. In addition, where the starting material employed con tains acarbon-carbon double bond either in the ring or in the Y-position,orboth, these double bonded carbon atoms may be converted to form anepoxy group with an oxygen atom by reacting the unsaturated precursorwith an organic peracid, such as perben-zoic acid, monoper- 'oxyphthalicacid, pertrifluoroacetic acid, and the like.

Further, if desired, the epoxy substituent may be cleaved to form thehydroxy derivative by treating the aforementioned epoxy compound withhydrogen in the presence of a catalyst selected from the metals of theeighth group of the periodic system, such as nickel, palladium,platinum, ruthenium or rhodium, which may be supported on a carrier,such as barium carbonate or charcoal. Reduc-.

tion of this nature is conducted in the presence'of a solvent, such asan alkanol, for example methanol or ethanol and, if so desired, underpressure.

The 7-R ,R -Y-N-R -5-norbornene-R -2,3-dicarboximides and correspondingnorbornane compounds used for the preparation of the novel series ofthis invention may be prepared from the corresponding 7-R1,R-Y-2-carboxamido-5-norbornene-3-carboxylic acids, or the correspondingnorbornane acids, as the case may be (wherein R and R are as definedabove), by ring closure. This may be advantageously accomplished byheating the acid in the presence :or absence of an inert organicsolvent, such as a hydrocarbon or halogenated hydrocarbon, for exampletoluene, benzene, xylene, hexane, heptane, tetrahydrofuran, dioxane,diethylether, chlorobenzene, carbon tetrachloride, chloroform, etc. Thetemperature conditions may vary from 50 C. up tothe boiling point of theparticular solvent employed. Means other than heat maybe usedtoeffectuate ring closure. These include treatment with suitabledehydrating agents such as a polyphosphoric acid, phosphoric acid,phosphorous oxyhalides phosphorous halides, thionyl chloride orphosphorous Reduction of this nature is conducted in the amine,ethylamine, or propylamine, preferably under reduced temperatureconditions, i.e. at 0 0-10." C. in the presence of a suitable inertorganic solvent, such as an alkanol, i.e. methanol, ethanol, propanol,acetone, an ether or a hydrocarbon such as benzene, toluene, xylene,hexane, mixtures thereof with each other, with Water or both.

Depending upon the conditions employed during the course of thereaction, the. novel compounds are obtained either in the form of thefree bases or salts thereof. The salts are converted to .the free basesin the usual manner, for example by reaction with alkali, such assodiumor potassium hydroxide. The bases can be converted to theirtherapeutically useful acid addition salts by reaction with anappropriate organic or inorganic acid.

The novel compounds may be converted into the corresponding quaternaryammonium compounds by reac ethyl bromide, propyl chloride; lower alkenylhalides allyl bromide; di-lower alkyl sulfates-dimethylsulfate,diethyisulrate; lower alkyl arylsulfonates-methyl p-toluolsulfonate oraralkyl halidesbenzyl chloride. The quaternizing reaction may beperformed in the presence or absence of a solvent, at room temperatureor under cooling, at atmospheric pressure or me closed vessel underpressure. Suitable solvents for this purpose are ethers'such asdiethylether and tetrahydrofuran, hydrocarbons such -as benzene andheptane, ketones such as acetone and butanone, lower'alkanols such asethanol, propanol, or butanol; or organic :acidjamides such as formamideor dimethylformamide. When lower alkyl halogenides are used asquaternizingagents, diethylether and benzene are the preferred solvents.

-The resulting quaternary ammonium compounds may be converted into thecorresponding quaternary ammonium hydroxides. This may be'accomplishedby reaction of the quaternary ammonium halides with silver oxide, byreaction of the sulfates with barium hydroxide,

preparation of the acid addition salts or, if desired, withpentoxideracid anhydrides, such as acetic anhydride or propionicanhydride; or organic'acid chlorides, such as, acetyl chloride orbenzoyl chloride. Ring closure, if desired, may also be advantageouslyaccomplished by treatment of the acid with one of the abovement-ioneddehydrating agents in the presence of an inorganic or organic base, e.g.an 'alkalior alkaline-earth metalhydroxide carbonate or bicarbonate,such as sodium hydroxide, potassium hydroxide, sodium carbonate,potassium carbonate, sodium bicarbonate, potassium bicarbonate; or saltsof organic acids, such as for example alkali-metal salts oralkaline-earth metal salts, i.e. sodiumacetate, potassium acetate,calcium propionate; or tertiary amines, such as for example pyridine,trimethylamine, triethylamine, etc.

The 7-R ,R -Y-2-carboxamido-S-norbornene-Ii-carboxylic acids and thecorresponding norbornane acids are I prepared from the known 7-R ,R-Y5-norbornene-2,3-

a mono lower =alkyl sulfate such as methylsulfate or ethylsulfate. Thequaternary ammonium compound may also be converted into anotherquaternary salt directly without conversion into the quaternary ammoniumhydroxide.

. Thus, a quaternary ammonium iodide may be reacted with freshlyprepared silver chloride to yield the quaternary ammonium chloride, orthe quaternary ammonium iodide may be converted into the correspondingchloride by treatment with hydrochloric acid in anhydrous methanol.

The novel compounds of the present invention may be converted to thecorresponding epoxides or N-oxides by treatment witha suitable oxidizingagent such as sodium peroxide orhydrogen peroxide; ozone; or aninorganic or organic peracid in the presence of an inert organicsolvent. Peroxides which are suitable oxidizing agents for this reactionare: hydrogen peroxide, sodium peroxide and the like. Peracids which maybe employed as oxidizing agents are monopersulfuric or p-toluene'-persulfonic and the organic percarboxylic acids, such as peracetic,performic, perbenzoic, monoperphthralic and pertrifluoroacetic. TheN-oxidizing reaction may be conveniently carried out in a diluent, suchas benzene, toluene, chloroform, ethylenedichloride, or an alk-anol,such as ethanol or methanol. The reaction reaches completion over a widelimit of time-namely, from a spontaneous completion up to a period ofone Week. Although temperature during the reaction is not critical, itshould be maintained within a range which will not result in furtheroxidation of the molecule, room temperature being preferred and mostconvenient.

Depending upon the starting materials employed, the isoindolino moietymay be either in exo or endo configuration with respect to the bicyclicmucleus in three-dimensional representation. It is to be understoodtherefore that the novel compounds, as generically described andclaimed, are intended to embrace both these configurations, it beingwell Within the purview of one skilled in the art to determine whichend-configuration is desired by initiating the process with theappropriate starting material. The examples given below are therefore tobe understood as illustrations of discrete species, not as limitationsupon the scope of the invention or as restrictive exemplifications ofexo or endo configurations of a given compound.

The novel compounds of the present invention are useful in the treatmentof peptic ulcer. This property has been demonstrated by inhibition ofulcer production in the rat by the method of Shay and also in ulcersproduced by the method of restraint. When used for their anticholinergicproperties, the compounds of the present invention may be employed indoses from about 30 to about 50 mg./kg. body weight. The novel compoundsmay be used in the form of pharmaceutical preparations which contain thecompounds, acid addition salts, quarternary ammonium compounds orN-oxides thereof in admixture with a pharmaceutical organic or inorganicsolvent or liquid carrier suitable for onal or parenteraladministnation. For formulating the preparations, one may employconventional tabletting, encapsulating and solvent carriers which do notreact with the new compounds, such as water, gelatin, lactose, starches,magnesium stearate, talc, vegetable oils, gums, polyalkylene glycols,normalsaline, syrup, etc. The pharmaceutical preparations may be in theform of tablets, pills, capsules or in liquid form, such as solutions,suspensions or emulsions. If desired, the novel compounds may beformulated with other therapeutically active substances. The actual doseadministered in therapy depends essentially on the condition of theindividual patient and the desires of the practicing physician.Optinrally, the dose administered may be from 25 to 150 milligrams threetimes daily by the oral route. Animal tests indicate that the novelcompounds have an extremely low order of toxicity, this being an LD of62 to 65 mg./kg. intnaperitone-ally in the mouse; 262 to 416 rug/kg.orally in the mouse; and 31 to 119 mg./ kg. intraperitoneally in therat.

For employing the above-defined compounds in the treatment of animals,it is generally more convenient to incorporate the novel compounds in aphysiologically compatible excipient such :as a dietary component of theanimal to be treated. Thus, the animal can receive its medication withits normal food intake. Alternatively, the novel compounds can beassociated in suitable dose amount with a physiologically compatibleexcipient which is edible but is not a normal dietary constituent andconsequently may not be physiologically utilizable, for example anion-exchange resin. Either type of blended mixture can readily beadministered to the animal by adding it to or mixing it with the feed ofthe animal in proper dose amount. If desired, the novel compounds can beblended with a fabricated animal feed in such amount that the medicatedfeed, when consumed in normal daily quantity by the animal, provides atherapeutically effective dose amount of the desired compound.

The following examples are illustrative of, but not limitative on, thenovel aspects of this invention.

Example I To a solution of sodium ethoxide prepared by adding 11.5 partsby weight of sodium to 300 par-ts by volume of absolute ethanol undernitrogen is added 91.2 parts by weight of benzophenone followed by asolution of 57.6

parts by weight of freshly prepared cyclopentadiene in parts by volumeof absolute ethanol. The addition is carried out with good stirring fora period of about ten minutes, during which time the undissolvedbenzophenone dissolves, yielding a dark red solution. After about tenminutes of stirring at room temperature, the product begins tocrystallize from the solution and after stirring an additional one andone-half hours at room temperature, the mixture is cooled in an ice-bathand kept at 0 C. for one-half hour. The product is then collected on afilter, Washed with. several portions of absolute alcohol, and dried,yielding diphenylfulvene, melting point 79.5 C. to 82 C. Concentrationof the mother liquors yields a second crop. The two crops are combinedand recrystallized from absolute alcohol to provide a pured-iphenylfulvene, melting point 81 C. to 82 C.

7 Example II A solution of 36.5 parts by weight of diphenylfulvene and15.5 parts by weight of maleic anhydride in parts Example III To 300parts by volume of methanol cooled below 0 C. in an acetone Dry-Ice bathis added a solution of 10 parts by volume of methylamine in 50 parts byvolume of cold methanol. To the resulting solution, cooled in an icebathwith stirring, is added 42.2 parts by weight of endo- 7diphenylmethylene 5 norborene-2,3 dicarbuxylic anhydride. The ice-bathis removed, and the mixture is allowed to come to room temperature andthen to stand overnight. The solution is concentrated to dryness, theresidue is slurried in Water, and the resulting aqueous suspension madeacidic with dilute hydrochloric acid. The precipitated acid is collectedon a filter, washed with water, and dried, yielding7-diphenyhnethylene-endo-2-methylcarbamido-5-norbornene-endo-3-carboxylicacid, melting point 160 C. to C.

Example .I V

To a mixture of 750 parts by volume of toluene and 150 parts by volumeof 2-propanol is added 27.5 parts by weight of7-diphenylmethylene-endo-2methylcarbamido-5-norbornene-endo-3-carb0xylic acid. The resulting solution is heated toboiling and the 2-propanol is slowly distilled from the mixture. Afterone and one-half hours all of the 2-propan-ol has been distilled and theremaining solution is heated under reflux for an additional two hours.The reaction solution is concentrated to dryness under reduced pressureand the residual oil is dissolved in methylene chloride, diluted withether and distilled to remove the bulk of the methylene chloride. Uponcooling the solution, the crystalline product separates. It is collectedon a filter, Washed with ether-petroleum ether and dried to giveendo-7-diphenylmethylene-5-norbornene-Nmethyl-2,3-dicarboxim-ide,melting point 171 C. to 174 C.

Example V To a slurry of 9.5 parts by weight of lithium aluminum hydridein 500 parts by volume of anhydrous ether is added rapidly, dropwise, asolution of 17.5 parts by weight ofendo-7-diphenylmethylene-5-norbornene-N-methyl-2,3- dicarhoximide in1500 parts by volume of anhydrous ether. The mixture is heated underreflux for two and one-half hours and is allowed to stand at roomtemperature overnight. To the reduction mixture is added care fullydropwise 50 parts by volume of ethyl acetate and then 20 parts by volumeof Water. The mixture is stirred at room temperature for three hours andthen filtered. The remaining inorganics are washed with ether and thecombined organic solution is dried .over magnesium sulfate, filtered andconcentrated to dryness under reduced pressure to giveendo-8-diphenylmethylene-2-methyl-3a,4,-7,7a-tetrahydro-4,7-methanoisoindoliue, melting point 74 C. to 77 C. Thebase is combined in methanol with 4.8 parts by weight of fumaric acidand the solution is diluted with ether, which affords crystals. Thesolid is filtered, washed three times with ether, and dried, yieldingendo-S-diphenylmethylene-Z-methyl-3a,4,7,7a-tetrahydro 1 4,7methanoisoindoline fumarate, melting point 203.5 C. to 205.5 C. (dec.).

Example VI To a boiling solution of 1.96 parts by weight of maleicanhydride in 30 parts by volume of xylene is added rapidly, dropwise, asolution of 4.6 parts by weight of diphenylfulvene in 36 parts by volumeof xylene. The solution is heated under reflux for five hours and thenconcentrated to dryness under vacuum. The addition of ether. to theresidue causes crystals to separate which are collected by filtration,washed with ether and dried to provide a mixture of adducts, meltingpoint 148 C. to 155 C., containing largely the endoisomer. Concentrationof the mother liquors and cooling provides a second, larger quantity ofproduct, melting point 135 C. to 142 C., which is largely the desiredexo-7-diphenylmethylene- 5-norbornene-2,3-dicarboxylic anhydride.

Example VII A solution of 0.6 part by volume of methylamine in 20 partsby volume of methanol cooled below C. in an racetone-Dry Ice bath istreated with 2.5 parts by weight ofexo-7-diphenytlmethylene-S-nOrbornene-Z,3-dicarboxylic anhydride. Thecold bath is removed, and the solution is allowed to come to roomtemperature and to stand for one hour. The solution is concentrated todryness under vacuum and the residue is partitioned between methylenechloride and dilute hydrochloric acid. Separation of the organic layerfollowed by drying over anhydrous magnesium sulfate and concentration todryness gives 7-diphenylrnethyleneexo-2-methylcarbamido-5-norborneneexo-3-carboxylic acid, melting point98 C. to 106 C. (dec.).

Example VIII A solution of 0.9 part by weight of 7-diphenylmethylene-exoZ-methylcarbamido-5-norbornene-exo-3-carboxylic acid in a mixture of 20parts by volume of benzene and parts by volume of absolute ethanol isheated under reflux for two hours and then concentrated to dryness undervacuum. The residue is dissolved in methylene chloride and the resultingsolution is washed with 5% sodium carbonate solution, dried overanhydrous magnesium sulfate and concentrated to dryness. Crystallization.of the residue from methylene chloride-ether gives exo 7diphenylmcthylene-S-norbornene-N-methyl-2,3- dicarrboximide, meltingpoint 154 C. to 157 C.

Example IX A mixture of 1.1 parts by weight of lithium aluminum hydridein 50 parts by volume of anhydrous ether is treated rapidly dropwisewith stirring with a solution of 2.0 parts by weight ofexo-7-diphenylmethylene-S-norbornene-N methyl-2,3-dicarboximide in 150parts by volume of anhydrous ether. The mixture is heated under refiuxfor three hours, cooled and carefully treated, dropwise, with stirringwith 5 parts by volume of water. After stirring for three hours, themixture is filtered and the insolubles are washed with ether.

The combined filtrate and washings are dried over magnesium sulfate andevaporated to dryness to give exo-8-diphenylrnethylene-2-methyl-3a,4,7,7a-tetrahydro-4,7-rnethanoisoindoline. The base isdissolved in hot 2-propanol and treated with 0.52 parts of fumaric acidin 2-propanol. Cooling the solution provides crystals. The solid isfiltered, washed with 2-propanol and then ether, and dried yieldingexo-S-dia phenylmethylene-2-rnethyl-3a,4,7,7a-tetrahydro-4,7-methanoisoindoline fumarate, melting at 176 C. to 178 C.

Example X 4.6 parts by weight of diphenylfulvene and 2.5 parts ExampleXI A solution of 14 parts by weight of endo-7-diphenylmethylene N-ethyl5-norbornene-2,S-dicarboximide in 1200 parts by volume of anhydrousether is added dropwise to a mixture of 7.7 parts by weight of lithiumaluminum hydride in 5 00 parts by volume of anhydrous ether. After theaddition the solution is heated under reflux for two hours and thenallowed to stand at room tempera, ture overnight. The reaction mixtureis hydrolyzed by the cautious dropwise addition or" 23 parts by volumeof water and is then allowed to stir at room temperature for two andone-half hours. The mixture is filtered and the inorganic salts arewashed thoroughly with ether. The filtrate is dried over anhydrousmagnesium sulfate, filtered, and concentrated to dryness under reducedpressure. There is obtained a light yellow viscous oil. On standing thisproduct slowly crystallizes. It is dissolved in petroleum ether andcooled until formation of crystals is complete. The crystals arecollected, Washed with petroleum ether and dried. There is obtainedendo-S-diphenylmethyleneZ-ethyl-3a,4,7,7a-tetrahydro-4,7-methanoisoindoline, melting point 88 C.to 92.5 C. Recrystallization from petroleum ether affords a purifiedproduct melting at 90.5 C. to 92.5 C.

Example XII A solution of 7.4 parts by weight of beta-phenethylamine inparts by volume of methanol is cooled to 0 C. and treated in portionswith 20 parts by weight of 'diphenylfulvene maleic anhydridecondensation product Endo 7 diphenylmethylene endoZ-(N-beta-phenethylcarbamido)-5'-norbornene endo B-carboxylic acid (23par-ts by weight) in 200 par-ts by volume of toluene is heated underreflux for four hours. Concentration of the solution to dryness yields agummy residue which is induced to crystallize with ether. The product iscollected on a filter, washed with ether and dried. There is obtainedendo-7-diphenylmethylene-N beta phenylethyl-S-norbornene-Z,3-dicarboximide, melting at 171 C. to 174 C. 7

Example XIV A sample bf endo-2-diphenylmethylene-S-norbornene-2,3-dicarboximide solution of 0.54 part by weight of potassium hydroxidein 15 par-ts by volume of water and 30 parts by volume of (2.5 parts byweight) is added to a 9 ethanol. To this solution is added 1.53 parts byweight of beta-phenethyl-bromide. The solution is stirred overnight atroom temperature. Additional potassium hydroxide andbeta-phenethylbromide are added and the solution is refluxed for two andone-half hours. The solution is concentrated in vacuo to one-halfvolume. The crystalline product is filtered and recrystallized frommethanol giving 1.5 parts by weight of endo-7-diphenylmethylene-N-betaphenethyl norbornene2,3-dicarboximide, melting point 174 C. to 176 C.

Example XV A solution of 4 parts by weight of endo-7-dipl1enylmethylene2 beta phenethyl-S-norbornene-2,3-dicarboximide in 75 parts by volume ofanhydrous tetrahydrofunan is added rapidly dropwise to a suspension of1.41 parts by weight of lithium aluminum hydride in 100 parts by volumeof the same solvent. After the addition is complete, the mixture isheated under reflux for sixteen hours and then allowed to cool. Thereduction mixture is hydrolyzed by the cautious addition of 4 parts byvolume of water to the well-stirred reaction mixture, and the mixture isthen allowed to stir for three hours. The precipitated inorganic saltsare collected on a filter, washed thoroughly with ether, and thecombined filtrate and washings are concentrated to dryness. The paleyellow gummy residue is combined with 50 parts by volume of 2-propanoland 0.82 part by weight of maleic acid, and the resulting solution isdiluted with ether, whereupon the crystals of the maleate precipitate.The crystals are collected on a filter, washed with ether, and dried,yielding endo 8 diphenylmethylene-2 beta-phenethyl-3a,4,7,7a-tetrahydro-4,7-methanoisoindoline maleate, melting at 178 C. to 179C.

Example X VI A solution of 4.13 parts by weight ofendo-7-diphenylmethylene N methyl 5 norbornene-2,3-dicarboximide in 90parts by volume of redistilled tetr-ahydrofunan is treated with 0.016part by weight of palladiumon-carbon and submitted to hydrogenation atatmospheric pressure. The mixture is stirred until the uptake ofhydrogen has slowed and a total of 303 parts by volume of hydrogen hasbeen consumed. The solution is filtered from the catalyst andconcentrated to dryness under reduced pressure. The residue is dissolvedin methylene chloride and ether, filtered and concentrated. Addition ofpetroleum ether provides crystals which are collected on a filter,washed with petroleum ether and air-dried. There is obtainedendo-7-diphenylmethylene-N-methyl-Z, 3-norbornane-dicarboximide, meltingat 137 C. to 141.5' C.

Example XVII A solution of 7.3 parts by weight ofendo-7-diphenylmethylene-N-methyl 2,3 norbornane dicarboximide in 600parts by volume of dry ether is added dropwise with stirring to amixture of 4.0 parts by weight of lithium aluminum hydride in 250 partsby volume of the same solvent. The mixture is heated u-nder reflux fortwo hours and allowed to stand at room temperature overnight. Hydrolysisis accomplished by the dropwise addition of 12 pants by volume of waterfollowed by stirring at room temperature for three hours. The inorganicsalts are removed by filtration and washed thoroughly with ether, andthe combined ethereal filtrate and washings are dried over anhydrousmagnesium sulfate, filtered, and evaporated to dryness under reducedpressure. There results a lightcolored gummy residue. A solution of thisproduct in ether is treated with a solution of 2.5 parts by weight offu-maric acid in 50 parts by volume of methanol. Further dilution ofthis mixture with ether afiords crystals, which are collected on afilter, Washed with ether and dried. There are obtained white crystalsof endo-8-diphenylmethylene-Z-methyl 321,4,5 ,6,7 ,7 a hexahydro-4,7-methanoisoindoline fumarate, melting at 191 C. to 192 C.

1 0 Example XVIII A solution of 5 par-ts by weight ofendo-7-diphenylmethylene-N-methyl-S-norbornene 2,3 dicarboximide in 75parts by volume of methanol plus 50 parts by volume of methylenechloride is treated with 0.25 part by weight of 10% palladium-on-carbonand subjected to hydrogen at three atmospheres pressure. After shakingthe mixture for fifteen minutes an amount of hydrogen corresponding tothe absorption of four atoms of hydrogen has been taken up. The solutionis filtered from. the catalyst and concentrated to dryness under reducedpressure. A solution of the residue in a mixture of methylene chlorideand ether leads to crystals, which are collected on a filter, washedwith ether and dried. After two recrystallizations from methanol-ether,pure endo-7-diphenylmethyl-'N-methyl-2,3-norbornane dicarboximide isobtained with a melting point of 206.5 C. to 209 C.

Example XIX Lithium aluminum hydride (2 parts by weight) is added toparts by volume of dry, freshly distilled tetrahydrofuran and to theresulting mixture with stirring is added a solution of 3.6 parts byweight of the imide described in Example XVIII in 300 parts by volume ofthe same solvent. After the addition is complete, the mixture is heatedunder reflux for five hours and then allowed to stand at roomtemperature overnight. Excess lithium aluminum hydride and the inorganiccomplexes are hydrolyzed by the cautious addition of 6 parts by volumeof water. After the mixture has stood at room temperature for fourhours, it is filtered and the precipitated inorganic salts are washedthoroughly with ether. The combined tetrahydrofuran filtrate andethereal washes are concentrated to dryness under reduced pressure. Theresulting basic product is dissolved in methanol and treated with r asolution of 1.3 parts by weight of fumaric acid in methanol. Upondilution with ether and cooling, crystals separate which are collectedon a filter, washed with ether, and dried, yielding 3.7 parts by weightof endo-8-diphenylmethyl-2methyl-3a,4,5,6,7,Aa-hexahydro 4,7methanoisoindoline furnarate with a melting point of 237 0.10

Example XX To a solution of 9 parts by weight of potassium hydroxide ina mixture of 250 parts by volume of water and 210 parts by volume ofethanol is added 29.6 parts by weight of7-isopropylidene-5-norbornene-2,3-dicarboximide. To this solution isadded rapidly 20.2 parts by Weight of dimethylsulfate. The mixture isstirred for fifteen minutes at room temperature and one hour at reflux.The solution is then concentrated in vacuo to remove the ethanol. Aftercooling, the product is filtered, washed well with water and dried invacuo over calcium chloride, alfording 27.9 parts by weight of productmelting at 78 C. 'to 123 C. After two recrystallizations from isopropylalcohol there is obtained 13 parts by weight of pure7-.isopropylidene-N-methyl-S-norbornene-2,3-dicarboximide, melting point142 C. to 143 C.

Example XXII A solution of 1.75 parts by weight of the inside describedin Example XXI in 200 parts by volume of anhydrous ether is addedrapidly dropwise to a mixture of ume of absolute ethanol.

l. l 1.6 parts by weight of lithium aluminum hydride in 50 parts byvolume of dry ether. After the addition is complete, the reactionmixture is heated under reflux for four hours andrthen left to stand atroom temperature overnight. The mixture is worked up by the carefuldropwise addition of 5 parts by volume of water followed byfiltrationfrom the inorganic salts and thorough washing of the insolublematerial with ether. The combined filtrates and washings areconcentrated to dryness and the residue is dissolved in acetone andtreated with an acetone solution of 0.8 part by weight of maleic acid.Concentration of this solution to a low volume followed by the additionof ether causes crystals of the m-aleate'salt to separate. The productis collected on a filter, washed with ether and dried. There is obtained1.22 parts by weight of 8-isopropylidene-Z-methyl-3a,4,7,7 a-tetrahydro4,7 methanoisoindoline fumarate, melting at 144 C. to 149 C.

Example XXIII To a solution of 2.3 parts by weight of sodium 100 partsby volume of absolute ethanol is added 21.7 parts by weight ofp-chlorobenzophenone and 50 parts by vol- The solution is stirred untilthe ketone is almost dissolved and a solution of 11.6 parts by Weight offreshly distilled cyclopentadiene in 25 parts by volume of cold absoluteethanol is added rapidly dropwise with stirring. The mixture is allowedto warm to room temperature and stir for four hours, during which timethe remaining starting material dissolves and orange crystals of theproduct separate. The mixture is concentrated under reduced pressure toa volume of about 75 parts by volume, cooled in ice, and the crystallineproduct collected on a filter, washed with ethanol, and dried. There isobtained 19 parts by weight of 6-p-chlorophenyl-6- phenylfulvene,melting at 73 C. to 74 C.

Example XXIV Example XXV A suspension of 13.8 parts by weight ofendo-7-p-chlorodiphenylmethylene-S-norbornene 2,3 *dicarboximide in 137parts by volume of ethanol is treated with 2.45 parts by weight ofpotassium hydroxide in 71 parts by volume of Water. The solution isstirred as 5.5 parts by weight of dimethylsulfate is added rapidly. Thegummy mixture is stirred at room temperature for one hour and at refluxfor one hour. It is then cooled, diluted with 120 parts by volume ofethanol and concentrated in vacuo at 35 C.

The precipitate is removed by filtration, Washed with ethanol andair-dried to give 13.6 parts by Weight ofendo-7-p-chlorodiphenylmethylene-N-methyl 5norbornene-2,3-dicarboximide, melting at 127 C. to 134 C. A

' sample purified by recrystallization from methylene chloride-e-ther-petroleum ether shows a melting point of 132 C.,to 136 C.

Example XXVI To a mixture of 6.6 parts by weight of lithium aluminumhydride in 200 parts by volume of dry ether is added dropwise withstirring a solution of 12.6 parts by weight of the imide described inExample XXV in 500 parts by volume of dry ether. After the addition iscomplete, the reaction mixture is heated to boiling for two hours andthen cooled to ice temperature. Hydrolysis is accomplished by thecareful dropwise addition of 19.7 parts by volume of water to thestirring reaction mixture. After the Water has been added, the mixtureis allowed to stir for two hours and is then filtered from theprecipitated inorganic salts which are Washed with several portions ofether. The combined filtrate and washings are evaporated to dryness toyield a residual oil. A portion of this product 6.9 parts by weight) isconverted to the maleate by solution in a small volume of acetone andtreatment with a solution of 2.3 partsby weight of maleic acid in'ether. The crystalline salt is collected on a filter and washed withether to give 7.8 parts by weight ofendo-S-p-chlorophenylmethylene-Z-methyl-3a,4,7,7atetrahydro-4,7-methanoisoindoline m'aleate, melting at C. to 161 C.

Example XX VII To a solution of sodium methoxide prepared by dissolv- 7ing 1 part by weight of sodium in 60 parts by volume of absolute ethanolis added 7.32 parts by weight of phenyl- 4-pyridylketone. ice-bath andtreated dropwise with stirring under nitrogen with a solution of 6.4parts by volume of freshly distilled cyclopentadiene in 20 parts byvolume of cold absolute methanol. After the addition is'complete, theresulting clear red solution is allowed to stir at ice temperature forthirty minutes and then warmed to room temperature and stir for anadditional hour. 'The mixture is filtered and the filtrate isconcentrated under reduced pressure until the ethanol has been removedto give 6-phenyl-6-(4-pyridyl)- fulvene- Example XX VIII To a solutionof sodium methoxide prepared by dissolving 1 part by weight of sodium in60 parts by volume of absolute ethanol is added 7.32 parts by weight ofphenyl-3-pyridylketone. This mixture is cooled to 0 C. in an ice-bathand treated dropwise with stirring under nitrogen with a solution of 6.4parts by volume of freshly distilled cyclopentadiene in 20 parts byvolume of cold absolute methanol. After the addition is complete, theresulting clear red solution is allowed to stir at ice temperature forthirty minutes and then warmed to room temperature and stir for anadditional hour. The mixture is filtered and the filtrate isconcentrated under reduced pressure until the ethanol has been removedto give 6-phenyl-6- 3-pyridyl) -fulvene.

Example XXIX To a solution of sodium methoxide prepared by dissolving 1part by weight of sodium in 60 parts by volume of absolute ethanol isadded 7.32 parts by weight of phenyl- 2-pyri-dylketone. This mixture iscooled to 0 C. in an ice-bath and treated drop wise with stirring undernitrogen with a solution of 6.4 parts byvolume of freshly distilledcyclopentadiene in 20 parts by volume of cold absolute methanol. Afterthe addition is complete, the resulting clear red solution is allowed tostir at ice temperature for thirty minutes and then warmed to roomtemperature and stir for an additional hour. The mixture is filtered andthe filtrate is concentrated under reduced pressure until the ethanolhas been removed to give 6-phenyl-6-(2- pyridyl) -fulvene.

' Example XXX A solution of 53 parts by Weight of 6-phenyl-6-(2-pyridyD-fulvene and 22.6 parts by weight of maleimide in 250 pants byvolume of benzene is heated under reflux for three hours. After cooling,the solid product is collected by filtration, washed with ether anddried giving 24.2 parts by weight of a bull-colored powder melting at210 C. to 216 C. Recrystallization from ethanol gives pure 7-(phenyl-2-pyridylmethylene) -5-norbornene-2,3-dicarboxirnide, meltingpoint 217 C. to 218 C.

. Example XXXI A solution of 1.67 parts by weight of potassium hydroxidein 48 parts by volume of water is added to a suspension of 8.0 parts byweight of the dicarboximide above This mixture is cooled to 0 C. in

in 83 parts by volume of ethanol and the mixture is stirred until theimide dissolves. Dimethylsul'fate, 2.54 parts by volume, is addedrapidly and the product begins to precipitate in five minutes. Themixture is stirred for two and one-half hours, when the pH is then 7,cooled in an ice-bath and the product is collected by filtration. It iswashed well with 40% aqueous ethanol and oven-dried to constant weightgiving 5.80 parts by weight of 7- (phenyl-2-pyridylmethylene) -N-methyl--norbornene-2,3- dicarboximide, melting at 169 C. to 170 C.

Example XXXII To a suspension of 6.5 parts by weight of lithium aluminumhydride in 200 parts by volume of anhydrous diethylether is added asolution of 11.7 parts by weight of 7- (phenyl-2-pyridylmethylene)-N-methyl-5-norbornene-2,3- dicarboximide in 700 parts by volume ofether and 190 parts by volume of dry tetrahydrofuran. The mixture isstirred at room temperature for two days and carefully decomposed with19.5 parts by volume of water. The solids are removed by filtration,washed with ether and the combined filtrate and washes are concentratedto dryness, giving 9.69 parts by weight of basic isoindoline product.The endoS-phenyl-2pyridylmethylene-2-methyl-3a,4,7,7.a-tetrahydro-4,7-methanoisoizndoline 'fumarate is prepared inisopropyl alcohol-ether and melts at 175 C. to 176 C. 7

Example XXXHI To a solution of 3.35 parts by weight of sodium in 100parts by volume of absolute ethanol is added a solution of 33.44 partsby weight of m-trifluoromethylbenzophenone in 85 parts by volume ofabsolute ethanol. A solution of 15.5 parts by Weight of freshlydistilled cyclopentadiene in 20 parts by Volume of ethanol is addedrapidly. The solution is stirred at room temperature for two and onehalfhours. The solution is concentrated to one-half volume under vacuum,diluted with water and extracted three times with ether. The organiclayer is dried over magnesium sulfate and the solvent is evaporated togive 6,6-m-trifluoromethyldiphenylfulvene.

Example XXXIV Example XXXV To a suspension of 315 parts by weight ofendo-7-mtrifluoromethyldiphenylmethylene 5 norbornene 2,3- dicarboximidein 320 parts by volume of ethanol is added a solution of 5.05 parts byweight of potassium hydroxide in 150 parts by volume of water. Themixture is heated gently to afford solution. At room temperature, 12.4parts by weight of dimethylsulfate is added. The mixture is heated toreflux and cooled. The ethanol is removed under vacuum and the oilyproduct is extracted into ether. The ether solution is washed withsodium bicarbonate and water. It is then dried over magnesium sulfate,filtered and concentrated to dryness in vacuo. A sample of the oilyresidue is taken up in ether and washed with dilute sodium hydroxide andwater. The organic solution is dried over magnesium sulfate andconcentrated in vacuo.

After recrystallization from ether-petroleum ether, 5.7

parts by weight ofendo-7-m-trifluoromethyld-iphenylmethylene-N-methyl-S-norbornene-Z,3-dicarboximideis obtained, melting point 135 C. to 137 C.

Example XXXVI To a suspension of 2.73 parts by weight of lithiumaluminum hydride in parts by volume of anhydrous other is added slowly asolution of 5.85 parts by weight of endo 7 mtrifluoromethyldiphenylmethylene N-methyl-5-norbornene-2,3-dicarboximide in 200 parts by volume of ether.The reaction mixture is stirred at room temperature for twenty-threehours and hydrolyzed by adding 8.2 parts by volume of water. Theinorganics are removed by filtration; the filtrate is dried overmagnesium sulfate and the solvent evaporated in vacuo.

The oily product is dissolved in ether and dilute hydrochloric acid. Theether solution is removed and further extracted with dilute hydrochloricacid. The combined acid fractions are made basic and extracted withether. The ether extract is dried and concentrated in vacuo to give 4.4parts by weight of oily product.

The oily base is combined with 1.35 parts by weight of maleic acid inacetone-ether. There is obtained 4.21 parts by weight of8-m-trifluoromethyldiphenylmethylene- 2 methyl 3a,4,7,7a tetrahydro 4,7methanoisoindoline maleate with a melting point of 143 C to l45.5 C.

Example XXX VII Under nitrogen 1.17 parts by weight of potassium isadded to parts by volume of dried tbutanol and is dissolved by heatingunder reflux for one hour. A solution of 5.90 parts by weight ofo-methylbenzophenone in 10 parts by volume of t-butanol is addedrapidly, followed by 4.45 parts by volume of freshly distilledcyclopentadiene. A white solid precipitates. The mixture is brought intosolution by heating to reflux and is then stirred under nitrogen atreflux for sixty-six hours. The dark solution is diluted with water andextracted twice with ether. The ether extracts are washed with water anddried over magnesium sulfate. Concentration of the ether solution gives6,'6-o-methyldiphenylfulvene.

Example XXXVIII A solution of 5.34 parts by weight of6,6-o-methyldiphenylfulvene and 1.90 parts by weight of maleimide in 50parts by volume of benzene is heated under reflux for three hours. Aftercooling and diluting with petroleum ether, the product crystallizes. Thecrystals are removed by filtration and washed with ether-petroleumetherto give 3.98 parts by weightofendo-7-omethy1diphenylmethylene-5-norbornene 2,3-dicarboximide,melting point 184 C. to 190 C. After two recrystallizations fromether-petroleum ether, to product melts at 185 C. to

. Example XXXIX To a suspension of 20.0 parts by weight ofendo-7-omethyldiphenylmethylene 5 norbornene 2,3 dicarboxirnide in 200parts by volume-of ethanol is added 3.98 parts by weight of potassiumhydroxide in 115 parts by volume of water. To this solution is added8.14 parts by weight of dimethylsulfate. The mixture is stirred at roomtemperature for one hour during which time the product crystallizes.After cooling in an ice-bath for one-half hour, the product is collectedon a filter, washed with aqueous alcohol and air-dried to give 15.8parts by weight of endo 7 o methyldiphenylmethylene N methyl-S-norbornene-Z,3-dicarboximide, melting point 161 C. to 162 C.

Example XL A solution of 14.68 parts by weight ofendo-7-o-methyldiphenylmethylene N methyl 5 norbornene 2,3 dicarboximidein 800 parts by volume of anhydrous ether is added slowly to asuspension of 7.75 parts by weight of lithium aluminum hydride in 200parts by volume of ether. Themixture is refluxed for five hours andallowed to stand at room temperature for sixteen'hours. The mix ture ishydrolyzed by the slow addition of 23.2 parts by volume of water. Theinorganics are removed by filtrabornene-Z,3-dicarboximide.

Example XLI To a solution of 2.3 parts by Weight of sodium in 80 partsby volume of ethanol is added a solution of 12 parts by weight ofacetophenone and 11.6 parts by weight of cyclo-pentadiene undernitrogen. After stirring for fortyfive minutes, the red solution isdiluted with water and extracted with ether. The extracts are evaporatedto dryness, affording 16 parts by weight of a red oil. The oil ispurified by distillation. The product, 6-methyl-6-phenylfulvene, has aboiling point of 90 C. to 108 C. at 2.5

of mercury.

Example XLII To a'solution of 1.44 partsby weight of maleimide in 30parts by volume of benzene is added a solution of 2.5

a parts by weight of 6-methyl-6-phenylfulvene in 15 parts by volume ofbenzene. This mixture is heated under reflux for three hours. Thesolution is evaporated to dryness in vacuo. Trituration with petroleumether affords crystalline 7-(1-phenylethylidene)-5-norbornene-2,3-dicarboximide which, after recrystallization from benzene, melts at 159C. to 161 C.

Example XLIII To a solution of 6.1 parts by weight of potassiumhydroxide, 180 parts by volume of water and 300 parts by volume ofethanol is added 23.4 parts by weight of 7-(1-phenylethylidene)--norbornene-2,3-dicarboximide. The mixture is warmedto achieve solution. After-cooling to roomtemperature, 11.8 parts byweight of dimethylsulfate is added. The mixture is stirred for two hoursat room temperature and two hours at reflux. The ethanol is removed invacuo. After cooling, the product is filtered, washed with ether anddried, yielding 23.2 parts by Weight ofendo-N-methyl-7-(1-phenethylidene)-5-nor- After two recrystallizationsfrom benzene-hexane, the pure product melts at 170 C. to 172 C.

Example XLIV 7 To a suspension of 6.5 parts by weight of lithium alumiumhydride in 95 parts by volume of dry tetrahydrot uran is added 9.6 partsby weight of endo-N-niethyl-7- (.1-phenylethylidene)-5-norbornene-2,3-dicarboxirnide in 130 parts by :volume of drytetrahydrofuran. The reaction mixture is heated at reflux for two hoursand stirred at room temperature for eighteen hours. It is then de-.composed by adding 20 parts by volume of water cautiously. The inorganicsalts are removed by filtration and Washed with ether. The totalfiltrate is evaporated to dryness in vacuo. The product is dissolved inether and extracted with dilute hydrochloric acid. The acid solution ismade basic and extracted with ether. .The organic solution is washedwith water and saturated sodium chloride solution, dried over magnesiumsulfate, filtered and evaporated to dryness in vacuo, yielding 7 partsby Weight of product as an oil. The oily base is dissolved in2-propanol-ether and treated with fumaric acid. There is thus obtained acrystalline fumarate, which is recrystallized from Z-propanol-ether to.give pure 3a,4,7,7a-tetrahydro 2 methyl 8 (l phenylethylidene) 4,7methanoisoindoline f urnarate, melting at 164 C. to 165 C.

' '=In a similar manner, following the procedures given above andcommencing with the appropriate starting material, there are preparedendo-8-phenyl-4-pyridylmethyl ene 2 methyl 3a,4,7,7a tetrahydro 4,7methano Example XLV A solution of 2.30 parts by weight ofdiphenylfulvene and 1.11 parts by Weight of N-methyl maleimide in 10parts by volume of benzene is allowed to stand at room temperature forfour days. to dryness under reduced pressure, treated with ether, and

the resulting solid is collected on a filter, washed with ether, anddried to yield endo 7-diphneylmethylene-N-methyl-S-norbornene-Z,3-dicarboximide, melting at 173 C. to 174 C.Concentration of the mother liquors gives an additional quantity ofmaterial.

Example XL VI A mixture of 10 parts by weight of diphenylfulvene and 4.2parts by Weight of maleimide in 75 parts by volume of benzene is heatedunder reflux for two hours, cooled and *diluted with ether. Thecrystalline product which separates is collected by filtration, washedwith ether and dried. Purification by recrystallization from ethylacetate gives endo-7-diphenylmethylene+5 norbornene-2,3-dicarboximide,melting point 204C. to 208 C.

Example XLVII V A mixture of 9.2 parts by Weight of diphneylfulvene and5.6 parts by weight of N-carbamoylmaleimide in 100 parts by volume ofbenzene is heated under reflux for two hours. The initial deep red colorof the fulvene disappears and the mixture thickens as the insolubleproduct separates. The mixture is cooled, diluted with ether, and

filtered, and the tan product is washed with ether and.

dried, giving endo-7-diphenylmethylene-N-carmbamoyl-5-norbornene-2,3-dicarboximide, melting at 200 C. to 210 C. withdecomposition.

Example XLVIII A slurry of 11.2 parts by weight ofthe N-carbamoylimide(supra) in 120 parts by volume of aqueous ethanol is boiled for twohours and 'then is concentrated to low volume,.' cooled, and filtered.The solid product is Washed with water and dried. There is obtained endo7 diphenylmethylene 5 norbornene 2,3 dicarboximide, melting at 204 C. to208 C. Recrystallization first from acetone and then from ethyl acetategives the pure imide (VII), melting at 208 C. to 210 C.

Example XLIX To a solution of 5.2 parts by weight of potassium hydroxidein 150 parts by volume of Water and 250 parts by volume of methanol isadded 23.6 parts by weight of endo 7 diphenylmethylene 5 norbornene 2,3dicarb oximide. parts by weight of dimethylsulfate dropwise withstirring. After about two minutes, a thick slurry is formed. Thismixture is allowed to stand for two hours at room temperature and it isthen refluxed for two hours. The ethanol is removed under reducedpressure, and the mixture is cooled and filtered, and the solid which iscollected is Washed with water and dried in the steam oven. There isobtained endo-7-diphenylmethylene-N-methyl-5norbornene-2,3-dicarboximide, melting at 166 C. to 171 C. withdecomposition. Recrystallization from ether atfords a product melting at176 C. to 177.5 C. (dec.).

Example L To 15 parts by weight of endo-7-diphenylmethylene-5-norbornene-2,3-dicarboximide almost completely dissolved in a mixture of350 parts by volume of hot ethanol and parts by volume of watercontaining.3.1 parts by weight of potassium hydroxide is added 4.1 partsby The solution is concentrated 7 To the resulting clear solution isadded 9.95

weight of ethylene chlorohydrin. The solution is refltuted for onehour,then treated three more times with 3.1 parts by weight of potassiumhydroxide in water and 4.1 parts by weight of ethylene chlorohydrin. Thetreatments are separated by approximately one hour of reflux.

The resultmt solution is concentrated in vacuo to remove ethanol. Theaqueous mixture is extracted with methylene chloride. The extracts areWashed with Water, dried over magnesium sulfate, filtered andconcentrated to dryness in vacuo. The crude product is recrystallizedfrom methylene chloride-ether, affording 12.9 parts by weight ofendo-7-diphenylmethylene N beta hydrox-yethylnorbornene-2,3-dicarboximide, melting point 171 C. to 172 C.

Example LI then hydrolyzed by the cautious addition of 18 parts byvolume of water. An additional 500 parts by volume of ether is added andthe mixture is stirred in an ice-bath for one 'half hour. The mixture isfiltered and the inorganics washed well with ether and benzene. Thefiltrate is then concentrated to dryness in vacuo.

The residual oil is dissolved in methylene chloride-ether and dilutehydrochloric acid. The ether layer is separated. The acid oil andsolution are combined, made basic with sodium hydroxide solution andextracted with methylene chloride. The extract is washed with water,dried over magnesium sulfate, filtered and concentrated to dryness invacuo affording 10.2 parts by weight of an oil.

The oil is dissolved in 25 parts by volume of methanol and treated witha solution of 3.5 parts by weight of fumaric acid in 30 parts by volumeof methanol. Dilution with ether and scratching affords crystals, whichare filtered, washed with ether and air-dried. The crystalline productis recrystallized from ethanol yielding 6.9 parts by weight ofendo-S-diphenylmethylene-3a,4,7,7a-tetrahydro 2 betahydroxyethyl-4,7-methanoisoindoline fum arate with a melting point of176 C. to 179 C.

xample LIZ To a slurry of 2.9 parts by weight of lithium aluminumhydride in 50 parts by volume of dried diethyleneglycol dimethylether isadded a solution of 5 parts by weight ofendo-7-diphenylmethylene-5-norbornene2,3-dicarboximide in 100 parts byvolume of the same solvent. The mixture is stirred at 80 C. for twohours and at room temperature for sixteen hours. The mixture ishydrolyzed by the dropwise addition of 9 parts by volume of water.Anhydrous ether (250 parts by volume) is added and the mixture isstirred at room temperature for one hour. It is then filtered. Theinorganic solids are washed well with ether and benzene and the filtrateis concentrated to dryness in vacuo. The oily product is dissolved inether and extracted twice with 2 N hydrochloric acid. The acid solutionis made basic with sodium hydroxide solution and extracted withmethylene chloride-ether. The extracts are dried over magnesium sulfate,filtered and concentrated to dryness in vacuo, affording 3.5 parts byweight of oily basic product.

The base is dissolved in acetone and treated with an acetone solution of1.36 parts by weight of maleic acid. The salt is filtered, washed withacetone-ether and dried, ailording 3.3 parts by'weight ofendQ-S-diphenylmethylene-3a,4,7,7a-tetrahydro-4,7-methanoisoindolinemaleate, melting at 186.5 C. to 190 C. after two recrystallizations fromethanol.

Example LIII To a solution of 12.35 parts by weight ofendo-7-diphenylmethylene N methyl 5 norbornene 2,3 dicarboximide inparts by volume of chloroform, cooled in an ice water-salt bath, isadded a solution of 5 parts by weight of perbenzoic acid in chloroform.After standing at room temperature for thirty-six hours, the chloroformsolution is washed three times with 5% sodium carbonate and once withwater. It is then dried over magnesium sulfate, filtered andconcentrated to dryness under reduced pressure. The product,endo-7-diphenylmethyl 7,alpha epoxy N methyl 5 norbornene-2,3-dicarboximide, is obtained as white crystals from methylenechloride-ether, and shows a melting point of 181.5 C. to 182.5 C.

Example LIV To a solution of 1 part by weight ofexo-7-diphenylmethylene-l l-methyl 5 norbornene-Zfl-dicarboximide in 10parts by volume of chloroform in an ice-water bath is added dropwise asolution of 0.405 part by weight of perbenzoic acid in chloroform. Afterstanding for twenty-four :hours at room temperature, the solution iswashed with 5% sodium carbonate solution, dried over magnesium sulfate,filtered and concentrated to dryness under reduced pressure. Theproduct, exo-7-diphenylmethylene 5,6 epoxy N methyl 2,3norbo-rnenedicarboximide, is crystallized from methylene chloridee'ther,yielding 0.92 part by weight, melting point 179.5 C. to 181.5 C.

Example LV Example LVI A 0.5 part by weight sample ofendo-7-diphenylmethyl- 7,alpha-epoxy-N-methyl-5-norbornenc-2,3dicarboximide is hydrogenated over 0.05 part by weight of platinum in 50parts by volume of methanol at atmospheric pressure.

After a rapid uptake of one equivalent of hydrogen, the reactionstopped. The solution is filtered and concentrated to dryness underreduced pressure. The product,endo-7-diphenylmethyl-7,alpha-epoxy-N-methyl-2,3norbornanedicarboximide, is crystallized from methylene chloride-etherin 100% yield, melting point 144 C. to 153 0., 176 C. to 178 C.

Example LVII A 2 parts by weight sample of endo-7-diphenylmethyl-7,alpha-opoxy-N-methyl-5-norbornene-2,3-dicarboximide is hydrogenated over0.5 part by Weight of 10% palladiumon-carbon in 100 parts by volume ofmethanol on a shaker. After six hours, the reaction is stopped and themixture is filtered. The catalyst is Washed well with methylene chlorideand the filtrate is concentrated to low volume under reduced pressure.The product is crystallized from methanol and is filtered. There isobtained 1.63 parts by weight ofendo-[7-diphenylmethyl-7-hydroxy-ll-mahyll-Zfi norbornanedicarboximide,melting point 276 C. to 280 C.

Example LVHI A 0.5 part by weight sample of endo-7-diphenylmethyl-7,alpha-epoxy-N-methyl-2,3 norbornanedicarboximide is hydrogenated over0.25 part by weight of 10% palladiumwto hours at 60 C., aflording aclear solution.

To 0.45 part by weight of endo-[7-diphenylmethyl-7-hydroxy-N-methyl]-2,3-norbornanedioarboximide in 25 parts by volume ofcold pyridine is added 0.135 part by volume of thionyl chloride,d-ropwise, with cooling. After standing at room temperature overnight,the solution is diluted with 50 parts by volume of water and extractedthree times with chloroform. The extracts are washed with dilute acid,dilute base, and water, dried over magnesium sulfate, filtered andconcentrated to dryness under reduced pressure. The product,endo-7-diphenylmethylene- N methyl 2,3-norbornanedicarboximide, iscrystallized from ether-petroleum ether, melting point 148C. to 151 C.

' Example LX To 30' parts by volume of 5butanol is added 4.7 parts byvolume of 0.3 M potassium-t-butoxide and 0.5 part by weight ofendo-[7-diphenylmethyl-7-hydroxy-N-rnethyl]-2,3-norbornanedioarboximide.The solution is refluxed for four hours and allowed to stand at roomtemperature overnight.

The alcoholic solution is diluted out with water, concentrated to removethe t-bu-tanol, and extracted with methylene chloride. The extracts aredried over magnesium sulfate, filtered and concentrated to drynessunder'reduced pressure, giving 0.22 part by weight of neutral materialwhich is crystallized from methylene chlorideether to give 0.12 part byweight of endo-[7-diphenylmethyl-7-hydr'oxy-N methyl] 2,3norbornanedicarboximide at 275 C. to 278 C.

The aqueous alkaline solution is acidified and extracted with methylenechloride. The extracts are dried over magnesium sulfate, filtered andconcentrated to dryness under reduced pressure, affording 0.4 part byweight of acidic product. This is dissolved in methanol-benzene andallowed to stand at room temperature for two weeks. During this time theproduct, 7-diphenylmethyl-7-hydroxy-3-[N methylcarbamoyl] -2norbornanecarboxylic acid is crystallized. After one recrystallizationfrom ethanolbe'nzene, 7-diphenylmethyl-7-hydroxy 3 [N-methylcarbamyl]-2-norborn'anecarboxylic acid shows a melting point of 198.5 C. to 201.5C.

. Example LXI A batch of 9.8 parts by weight ofendo-[7-diphenylmethyl-7-hydroxy-N-methyl] 2,3 norbornanedicarboximideis added to a solution of 50 parts by weight of potassium hydroxide in250 parts by volume of water and 250 parts by volume of ethanol andrefluxed for six hours. The solution is then concentrated under reducedpressure to remove the ethanol and is diluted with 100 parts by volumeof water. The solution is cooled and acidified with hydrochloric acid.The crystalline product is filtered and consists of7-diphenylmethyl-7-hydroxy-2,3- no'rbornanedicarboxylic acid, meltingpoint 135 C. to 142 C. (dec.)..

The normal beta-phenethylamine salt of7-diphenylmethyl-7-hydroxy-2,3-norbornanedicarboxylic acid is preparedand, after two recrystallizati-ons from ethanol, is melted at 135.5 C.to 137.5 C.

Example LXII To a 1 part by weight sample of 7-diphenylmethyl-7-hydroxy-2,3-norbornanedicarboxylic acid is added parts by volume ofacetyl chloride. The mixture is heated for The acetyl chloride is thenboiled oil and the residue dried 20 under reduced pressure. The residueis dissolved in chloroform and washed three times with 5% sodiumbicarbonate. The chloroform solution is dried over magnesium sulfate,filtered and concentratedto dryness under reduced pressure, yielding0.75 parts by weight of noncrystalline neutral product. This material iscrystallized in petroleum ether and is twice recrystallized frommethylene chloride-ether, melting point 224 C. to 225.5 C.

Example LXIII A solution of 4.5 parts by weight of 7 adiphenylmethyl- 7hydroxy-2,3-norbornanedicarboxylic. acid in 100 parts by volume ofmethanol is titrated withan ethereal solution of 'diazomethane until theyellow color of the reagent persists. After standing at room temperatureover night, the solution is concentrated to dryness under reducedpressure. They oily product is dissolved in methylene chloride-ether andwashed twice with 5% sodium bicarbonate solution and once with water.organic solution is dried over magnesium sulfate, and concentrated todryness under reduced pressure, aifording 100% ofdimethyl-fidiphenylmethyl-7-hydroxy-2,3-norbornanedicarboxylate, an oil.

Example LXIV To a solution of 5.6 parts by weight of sodium in 60 pantsby volume of absolute methanol is added a solution of 3 parts by weightof :dimethyl-7-diphenylmethyl 7-hydroxy-2,3-norbornanedicarboxylate. Thesolution is reiluxedfor five hours and allowed to stand at roomtemperature overnight. It is then diluted with water, concentrated toremove the methanol, and refluxed for two hours. The aqueous solution isthen washed twice with ether, acidified with dilute hydrochloric acidand extracted three times with methylene chloride-benzene. The extractsare concentrated to dryness under reduced pressure. The product iscrystallized from methylene chloride, affording the A isomer of7-diphenylmethyl-7- hydroxy-2,3-norbornanedicarboxylic acid, meltingpoint 140 C. to 145 C. The mother liquor affords the B isomer of7-diphenylrnethyl-7 hydroxy-2,3-norbornanedicarboxylic acid, meltingpoint 258 C. to 260 C.

Example LXV A parts by weight sample of the A isomer of 7-diphenylmethyl-7-hydroxy 2,3 -'norbornanedicar-boxylic acid is treatedwith 0.5 part by volume of acetyl chloride and warmed at 60 C. for twohours. The acetyl chloride is boiled off and the product is dried underreduced pressure. It is then dissolved in chloroform and extracted threetimes with 5% sodium bicarbonate. The aqueous solution is acidified withdilute hydrochloric acid and the gummy solid is crystallized frommethylene chloride. After two recrystallizations from aqueous ethanol,the product, the A isomer of 7-diphenylmethyl-7-hydroxy-2,3-norbornanedicarboxylic acid, gamma-lactone, melts at 191 C. to 192.5C.

Example LXVI A parts by weight sample of the B isomer of 7-diphenylmethyl-7-hydroxy 2,3 norbornanedicarboxylic acid, gamma-lactoneis treated with 0.5 part by volume of acetyl chloride. Even afterwarming for two hours, solution is not obtained. The mixture is thenwarmed overnight at 60 C. The crystalline product is dried under reducedpressure, affording 100% of the B isomer of 7-diphenylmethyl-7-hydroxy2,3 norbornanedicarboxylic acid, gamma-lactone, melting point 253 C. to259 C.

Example LX VII To 7 parts by weight of enclo-S-diphenylmethylene-2-methyl-3a,4,7,7a-tetrahydro 4,7 methanoisoindoline in 70 parts by volumeof chloroform in an ice-water bath is added a chloroform solution ofperbenzoic acid. After standing for three days at room temperature, thesolution is washed well with 5% sodium carbonate solu- 21 tion andconcentrated under reduced pressure. The product is dissolved inmethylene chloride, dried over magnesium sulfate, filtered andconcentrated to dryness under reduced pressure, atiording about 12 partsby weight of crude products."

The crude products are dissolved in benzene and shaken with dilutehydrochloric acid, giving three layers, an aqueous layer containinginsoluble material, an oily benzene-insoluble layer, and a benzenesolution. The benzene layer is separated.

The other two layers are made basic with aqueous sodium hydroxide andextracted with methylene chloride. The extracts are washed with water,dried over magnesium sulfate, filtered and concentrated to dryness underreduced pressure, igivin-g 9.1 parts by weight of oily basic product.

The basic product is dissolved in acetone and treated with an acetonesolution or 2.6 parts by weight of maleic acid. After diluting withether, a crystalline salt is obtained. The salt is recrystallized twicefrom methanol, affording endo B-diphenylmet-hylene-S,6-epoxy-2-methyl-3a,4,5,6,7,7a-hexahydro-4,7 methanoisoindoline maleate, melting point151 C. to 152 C.

Example LXVIII To a slurry of 1.62 parts by weight of lithium aluminumhydride in 25 parts by volume of tetrahydrofuran is added a solution of2 parts by weight of endo-7sdiphenylmethyl-7,alpha-expoxy-N methyl 5nor-bornene- 2,3-dicanboximide in 25 parts by volume of tetrahydrofuran.The mixture is stirred at room temperature for forty-eight hours andthen hydrolyzed by the cautious addition of 5 parts by volume of water.The mixture is stirred for two hours and filtered, and the inorganicsare washed thoroughly with tetrahydrofuran. The filtrate is concentratedto dryness under reduced pressure. The oily product is dissolved inether, dried over magnesium sulfate, filtered and concentrated todryness under reduced pressure, afiording 90% of a viscous oily product.

A fumarate salt of the product is prepared in isopropyl alcohol. Afterone recrystallization from isopropyl alcohol, the white, crystallinefumarate of endo-8-diphenylmethyl-3a,4,7,7a-tetrahydro-2-methyl 4,7methanoisoindolinol shows a melting point of 217 C. to 220 C. (dec.).

Example LXIX To a slurry of 1.07 parts by weight of lithium aluminumhydride in 50 parts by volume of tetrahydrofuran is added a solution of2 parts by weight of endo-7-diphenylmethyl-7,alpha-epoXy-N-methyl 2,3norbornane dLcarboximide in 75 parts by volume of tetrahydrofuran. Afterstanding at room temperature for forty-eight hours, the mixture ishydrolyzed by the cautious addition of 3.1 parts by volume of water.After stirring for three hours, the mixture is filtered and theinorganics washed well with tetrahydrofuran. The filtrate isconcentrated under reduced pressure. The product is dissolved in other,dried over magnesium sulfate, filtered and concentrated to dryness underreduced pressure, affording endo-8-diphenylmethyl-3a,4,5,6,7,7a-hexahydro 2 methyl-4,7-rnethanoisoindolinol.

Example LXX To a solution of 3.7 parts by weight of lithium aluminumhydride in 35 parts by volume of tetrahydrofuran is added dropwise asolution of 7 parts by weight of endo- [7diphenylmethyl-7-hydroxy-N-rnethyl] 2,3 norbornanedicarboximide in 150parts by volume of warm tetrabydrofuran. The solution is stirred for tWohours at room temperature and at reflux for forty-five minutes and thenallowed to stand at room temperature overnight.

The reaction mixture is then hydrolyzed by the cautious addition of 11parts by volume of water. The mixture is filtered and the inorganicswashed well with tetra- 22 hydrofuran and benzene. The filtrate isconcentrated to dryness under reduced pressure. The oily product isdissolved in methylene chloride-ether and dried over ma nesium sulfate.After filtration, the solution is concentrated to dryness under reducedpressure, affording 6.6 parts by weight of oily product.

The fumarate of the oily product is prepared in methanol-ether, givingendo-[8-diphenylmethyl-3a,4,5,6,7,7ahexahydro-Z-methyl 4,7methano-8-isoindolinol] fumarate, melting point 219 C. to 221 C. (dec.).

Example LXXI A sample (6.5 parts by weight) of endo-S-diphenylmethylene2 methyl-3a,4,7,7a-tetrahydro 4,7 methanoisoindoline is dissolved inparts by volume of methanol-benzene and treated with 3.7 parts by weightof methyl iodide. The solution is stirred for one hour at roomtemperature and fifteen minutes at reflux. The solution is concentratedin vacuo and diluted with ether. The product,endo-8-diphenylrnethylene-2,2-dimethyl-3a,4,7,7a-tetrahydro-4,7-methanoisoindolinium iodide, is filtered, washedwith ether and dried, yielding 8.5 parts by weight, melting at 260 C. to262 C. with decomposition.

' What is claimed is:

l. A member selected from the group consisting of 2 Ra,4,7,7a-tetrahydro-4,7-(R ,R -Y)-R isoindolines, the corresponding3a,4,5,6,7,7a-hexahydro compounds, their N-oxides, therapeuticallyactive acid addition salts and quaternary ammonium compounds selectedfrom the group consisting of lower alkyl halides, lower alkenyl halides,di-lower alkyl sulfates, lower alkyl tolyl sulfonates and thecorresponding hydroxides, wherein each of R R R and R is,interchangeably, a member se ected from the group consisting ofunsubstituted phenyl, tolyl and naphthyl and substituted with a memberof the group consisting of hydroxy, lower alkyl, lower alkoxy, loweralkenyloxy, oxa-lower-alkoxy, halo, di-lower alkylamino and amino-loweralkoxy; lower alkyl; hydroxy lower alkyl, amino-lower alkyl;pyrr-olidyl; piperidyl; morpholyl; thiamorpholyl; pyridyl; thienyl;furyl; piperazinyl; benzyl; phenethyl; each of R and R is further,interchangeably, a member of the group consisting of hydrogen,carboxamide and styryl; R is further, a member of the group consistingof hydroxy, amino and an oxygen atom joined through single bonds to eachof two adjacent carbon atoms; Y is a member of the group consisting ofhydroxy lower alkyl and epoxy lower alkyl chain from two to seven carbonatoms attached to the isoindoline nucleus at the 4,7-positions through asingle carbon atom.

2. 8-diphenyl lower allrylene-Z-loweralkyl-3a,4,7,7-atetrahydro-4,7-lower alkanoisoindoline.

3. S-di-phenyl alkylene-Z-lower beta-phenethyl-3a,4,7,7a-tetrahydro-4,7-lower alkanoisoindoline.

4. S-di-phenyl lower alkylene-Z-lower alkyl-3a,4,5,6,7,7a-hexahydro-4,7-methanoisoindoline.

5. 8-di-phenyl lower alkyl-3a,4,5,6,7,7a-hexahydro-4,7 loweralkanoisoindoline.

6. 8-iso-lower alkylidene-Z-methyl-Ba,4,7,7a-tetrahydro- 4,7-loweralkanoisoindoline.

7. S-phenyl pyridylmethylene-Z-lower'alkyl-3a,4,7,7atetrahydro-4,7-lower alkanoisoindoline.

8. 8 diphenylrnethylene-Z-methyl-SaA,7,7a-tetrahydro-4,7-methanoisoindoline.

9. 8 diphenylmethylene-2,B-phenethyl-3a,4,7,7a-tetra- References Citedin the file of this patent Rice et al.: J. Org. Chem, vol. 19, pp.884-893 (1954).

UNITED STATES PATENT ()FFICE CERTIFICATE OF CORRECTION Patent N0 3 100776 August 13 1963 George Ireland Poos It is hereby certified that errorappears in the above numbered petent requiring correction and that thesai d Letters Patent should read as corrected below.

In the heading to the printed specification line 2 for 2R 3a 4"?a" read2R -3a,4,7 7acolumn 5, line 5 for "mucleus" read nucleus column 19 line'74 for "wto" read two column 20, line 20 9 after "sulfate insertfiltered column 21 line 29 for "expoxy" read epoxy column 22., line 27,

Signed and sealed this 21st day of April 1964.

(SEAL) Attest:

ERNEST W0 SWIDER EDWARD J BRENNER Attesting Officer Commissioner ofPatents

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF 2 -R3A,4,7,7A-TETRAHYDRO-4,7-(R1, R2-Y)-R4 - ISOINDOLINES, THECORRESPONDING 3A,4,5,6,7,7A-HEXAHYDRO COMPOUNDS, THEIR N-OXIDES,THERAPEUTICALLY ACTIVE ACID ADDITION SALTS AND QUATERNARY AMMONIUMCOMPOUNDS SELECTED FROM THE GROUP CONSISTING OF LOWER ALKYL HALIDES,LOWER ALKENYL HALIDES, DI-LOWER ALKYL SULFATES, LOWER ALKYL TOLYLSULFONATES AND THE CORRESPONDING HYDROXIDES, WHEREIN EACH OF R1, R2, R3AND R4 IS, INTERCHANGEABLY, A MEMBER SELECTED FROM THE GROUP CONSISTINGOF UNSUBSTITUTED PHENYL, TOLYL AND NAPHTHYL AND SUBSTITUTED WITH AMEMBER OF THE GROUP CONSISTING OF HYDROXY, LOWER ALKYL, LOWER ALKOXY,LOWER ALKENYLOXY, OXA-LOWER-ALKOXY, HALO, DI-LOWER ALKYLAMINO ANDAMINO-LOWER ALKOXY; LOWER ALKYL; HYROXY LOWER ALKYL, AMINO-LOWER ALKYL;PYRROLIDYL; PIPERIDYL; MORPHOLYL; THIAMORPHOLYL; PYRIDYL; THIENYL;FURYL; PIPERAZINYL; BENZYL; PHENETHYL; EACH OF R3 AND R4 IS FURTHER,INERCHANGEABLY, A MEMBER OF THE GROUP CONSISTING OF HYROGEN, CARBOXAMIDEAND STYRYL; R4 IS FURTHER, A MEMBER OF THE GROUP CONSISTING OF HYDROXY,AMINO AND AN OXYGEN ATOM JOINED THROUGH SINGLE BONDS TO EACH OF TWOADJACENT CARBON ATOMS; Y IS A MEMBER OF THE GROUP CONSISTING OF HYDROXYLOWER ALKYL AND EXPOXY LOWER ALKYL CHAIN FROM TWO TO SEVEN CARBON ATOMSATTACHED TO THE ISOINDOLINE NUCLEUS AT THE 4,7-POSITIONS THROUGH ASINGLE CARBON ATOM
 7. 8-PHENYL PYRIDYLMETHYLENE-2-LOWERALKYL-3A,4,7,7ATETRAHYDRO-4,7-LOWER ALKANOISOINDOLINE.